FROM THE LANCET
The investigational interleukin-6 inhibitor sirukumab proved effective and safe for rheumatoid arthritis patients who failed to respond to or were intolerant of multiple previous therapies in a phase III trial reported online in The Lancet.
These patients are “exceptionally treatment-resistant” and have “substantial clinical needs with the lowest chance of treatment success,” said first author Daniel Aletaha, MD, of the division of rheumatology at the Medical University of Vienna, and his associates.
Two different doses of sirukumab provided rapid and sustained improvements in rheumatoid arthritis (RA) signs and symptoms, physical function, and health status. These were accompanied by improvements in physical and mental well-being, a result that is particularly relevant for RA patients, who have a high prevalence of mood disorders. It has been estimated that 39% of RA patients have moderate to severe depressive symptoms, the investigators noted.
They assessed sirukumab in the manufacturer-funded trial involving 878 adults treated and followed at 183 centers in 20 countries across North America, Europe, Latin America, and Asia. These patients included 59% who had failed to respond to or had been intolerant of two or more biologic disease-modifying antirheumatic drugs (39% to two or more tumor necrosis factor inhibitors) and numerous other RA treatments.
The patients in the study, called SIRROUND-T , were randomly assigned to receive 50 mg sirukumab every 4 weeks (292 patients in the low-dose group), 100 mg sirukumab every 2 weeks (292 in the high-dose group), or matching placebo (294 patients in the control group) via subcutaneous injections for 52 weeks. Patients receiving placebo whose condition worsened were allowed an “early escape,” a blinded switch to either dose of the active drug for the remainder of the trial. At week 24, patients remaining in the placebo groups also were randomly assigned in a blinded manner to switch to active treatment ( Lancet. 2017 Feb 15. doi: 10.1016/S0140-673630401-4 ). All patients were allowed to continue using any concomitant disease-modifying antirheumatic drugs (DMARDs). At baseline, only 80% were using a conventional synthetic DMARD, and about 25% of patients in each group were not taking methotrexate.
The primary efficacy endpoint was the proportion of patients achieving an ACR20 response (a 20% or greater improvement in swollen joint count and tender joint count plus a 20% or greater improvement in at least three factors: pain, patient-assessed disease activity, physician-assessed disease activity, patient-assessed physical function, and C-reactive protein levels) at week 16. Sirukumab achieved higher levels of response in both the low-dose (40% of patients) and high-dose (45%) groups than did placebo (24%).
In addition, significantly higher proportions of patients receiving active treatment achieved the secondary endpoints of ACR20, ACR50, and ACR70 at week 24. Greater improvements, including remission, also were noted with sirukumab than with placebo according to the Simplified Disease Activity Index, ACR/EULAR criteria, and the Health Assessment Questionnaire–Disability Index. And significantly greater improvements also were seen in the Functional Assessment of Chronic Illness Therapy–Fatigue score, the 36-Item Short Form Health Survey, the Work Limitations Questionnaire, the EuroQol-5 Dimension questionnaire, and the EuroQol Health State Visual Analogue Scale.
In both active-treatment groups, all of these improvements were noted as early as within 2 weeks of starting treatment and persisted through follow-ups at week 24 and week 52.
Rates of adverse events, serious adverse events, and adverse events leading to treatment discontinuation were similar across the three study groups. Infections (primarily pneumonia) and infestations were the most frequent adverse events leading to discontinuation. No cases of tuberculosis or serious opportunistic infections were reported. Both doses of sirukumab induced declines in neutrophil, platelet, and white blood cell counts, as well as increases in alanine aminotransferase, aspartate aminotransferase, bilirubin, cholesterol, and triglycerides. Nine patients had hypersensitivity reactions, including one classified as serious dermatitis; all of these patients were taking the high dose of sirukumab. One of the five patient deaths that occurred, a fatal case of pneumonia, was considered possibly related to sirukumab.
This trial was funded by Janssen and GlaxoSmithKline, which also participated in the study design, data collection and analysis, and writing the results. Dr. Aletaha reported serving as a consultant for or receiving research support from AbbVie, Pfizer, Grünenthal, Merck, Medac, UCB, Mitsubishi/Tanabe, Janssen, and Roche. His associates reported ties to numerous industry sources.